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Premenopausal women with idiopathic osteoporosis (PreMenIOP) have marked deficits in skeletal microstructure. We have reported that sequential treatment with teriparatide and denosumab improves central skeletal bone mineral density (BMD) by dual-energy X-ray absorptiometry and central QCT in PreMenIOP. We conducted preplanned analyses of high-resolution peripheral quantitative computed tomography (HR-pQCT) scans from teriparatide and denosumab extension studies to measure effects on volumetric BMD (vBMD), microarchitecture, and estimated strength at the distal radius and tibia. Of 41 women enrolled in the parent teriparatide study (20 mcg daily), 34 enrolled in the HR-pQCT study. HR-pQCT participants initially received teriparatide (N = 24) or placebo (N = 10) for 6 months; all then received teriparatide for 24 months. After teriparatide, 26 enrolled in the phase 2B denosumab extension (60 mg q6M) for 24 months. Primary outcomes were percentage change in vBMD, microstructure, and stiffness after teriparatide and after denosumab. Changes after sequential teriparatide and denosumab were secondary outcomes. After teriparatide, significant improvements were seen in tibial trabecular number (3.3%, p = 0.01), cortical area and thickness (both 2.7%, p 0.001), and radial trabecular microarchitecture (number: 6.8%, thickness: 2.2%, separation: -5.1%, all p 0.02). Despite increases in cortical porosity and decreases in cortical density, whole-bone stiffness and failure load increased at both sites. After denosumab, increases in total (3.5%, p 0.001 and 3.3%, p = 0.02) and cortical vBMD (1.7% and 3.2%; both p 0.01), and failure load (1.1% and 3.6%; both p 0.05) were seen at tibia and radius, respectively. Trabecular density (3.5%, p 0.001) and number (2.4%, p = 0.03) increased at the tibia, while thickness (3.0%, p = 0.02) increased at the radius. After 48 months of sequential treatment, significant increases in total vBMD (tibia: p 0.001; radius: p = 0.01), trabecular microstructure (p 0.05), cortical thickness (tibia: p 0.001; radius: p = 0.02), and whole bone strength (p 0.02) were seen at both sites. Significant increases in total vBMD and bone strength parameters after sequential treatment with teriparatide followed by denosumab support the use of this regimen in PreMenIOP. © 2022 American Society for Bone and Mineral Research (ASBMR).

Context Premenopausal women with idiopathic osteoporosis (PreMenIOP) have marked deficits in bone density, microstructure, and strength. Objective To define effects of treatment with teriparatide followed by denosumab on lumbar spine (LS) volumetric bone mineral density (vBMD) and stiffness by finite element analysis assessed on central quantitative computed tomography (cQCT) scans. Design, Settings, and Participants Ancillary analysis of baseline, post-teriparatide, and post-denosumab cQCT scans from a randomized trial of 41 women allocated to teriparatide (20 mcg daily; n = 28) or placebo (n = 11). After 6 months, those on teriparatide continued for 18 months, and those on placebo switched to teriparatide for 24 months. After completing teriparatide, 33 enrolled in a Phase 2B extension with denosumab (60 mg every 6 months) for 12 months. Main Outcome Measures Primary outcomes were percentage change from baseline in LS trabecular vBMD and stiffness after teriparatide and between end of teriparatide and completing denosumab. Percentage change from baseline in LS trabecular vBMD and stiffness after sequential teriparatide and denosumab were secondary outcomes. Findings There were large increases (all Ps Conclusions The large and statistically significant increases in volumetric density and stiffness after sequential treatment with teriparatide followed by denosumab are encouraging and support use of this regimen in PreMenIOP.

Context We have previously reported that teriparatide is associated with substantial increases in bone mineral density (BMD) at the lumbar spine (LS), total hip (TH), and femoral neck (FN) and small declines at the distal radius in 41 premenopausal women with idiopathic osteoporosis (IOP), all severely affected with low trauma fractures and/or very low BMD. Effects of teriparatide dissipate if not followed by antiresorptives. Objective To assess the effects of 12 and 24 months of denosumab in premenopausal women with IOP completing 24 months of teriparatide. Methods This was a preplanned phase 2B extension study. Premenopausal women with IOP who had completed a course of teriparatide received denosumab 60 mg every 6 months over 24 months. The main outcome measure was within-group change in BMD at the LS at 12 months. Secondary outcomes include change in 12-month BMD at other sites, 24-month BMD at all sites, trabecular bone score (TBS), and bone turnover markers (BTMs). Results After completing teriparatide, 32 participants took denosumab for 12 months and 29 for 24 months, with statistically significant increases in BMD at the LS (5.2 ± 2.6% and 6.9 ± 2.6%), TH (2.9 ± 2.4% and 4.6 ± 2.8%), and FN (3.0 ± 3.8% and 4.7 ± 4.9%). Over the entire 24-month teriparatide and 24-month denosumab treatment period, BMD increased by 21.9 ± 7.8% at the LS, 9.8 ± 4.6% at the TH, and 9.5 ± 4.7% at the FN (all P < .0001). TBS increased by 5.8 ± 5.6% (P < .001). Serum BTM decreased by 75% to 85% by 3 months and remained suppressed through 12 months of denosumab. Denosumab was generally well tolerated. Conclusion These data support the use of sequential teriparatide and denosumab to increase BMD in premenopausal women with severe osteoporosis.

Context: Populations severely affected by COVID-19 are also at risk for vitamin D deficiency. Common risk factors include older age, chronic illness, obesity, and non-Caucasian race. Vitamin D deficiency has been associated with risk for respiratory infections and failure, susceptibility and response to therapy for enveloped virus infection, and immune-mediated inflammatory reaction. Objective: To test the hypothesis that 25-hydroxyvitamin D[25(OH)D] deficiency is a risk factor for severity of COVID-19 respiratory and inflammatory complications. Design: We examined the relationship between prehospitalization 25(OH)D levels (obtained 1–365 days prior to admission) and COVID-19 clinical outcomes in 700 COVID-19 positive hospitalized patients. Primary Outcomes: Discharge status, mortality, length of stay, intubation status, renal replacement. Secondary Outcomes: Inflammatory markers. Results: 25(OH)D levels were available in 93 patients [25(OH)D:25(IQR:17–33)ng/mL]. Compared to those without 25(OH)D levels, those with measurements did not differ in age, BMI or distribution of sex and race, but were more likely to have comorbidities. Those with 25(OH)D

Engaging children in meaningful occupations is a means of improving their participation. The objective of this study is to assess differences in dimensions of meaning of occupations—challenge, value, felt time, and autonomy—between children with and without neurodevelopmental disorders and their associations with the participation of each group. Thirty children with neurodevelopmental disorders (autism spectrum disorder [ASD]/attention deficit hyperactive disorder [ADHD]) and 30 typically developing children ( M age = 9.37 ± 1.41 years) reported regarding dimensions of meaning of occupations. Their parents reported regarding children’s participation. Children with neurodevelopmental disorders attach different meanings to their everyday activities than their typically developing peers, with a large effect size ([Formula: see text] = .07–.12). For children with neurodevelopmental disorders, the value and autonomy dimensions of meaning were correlated with participation. The findings expand knowledge of occupational meaning and participation among children. To optimize the participation of children, occupational therapists should facilitate autonomy and engage children in activities that they value.

Postmenopausal osteoporosis (PMOP) therapies are frequently evaluated by bone mineral density (BMD) gains against patients receiving placebo (calcium and vitamin D supplementation, a mild bone turnover-suppressing intervention), which is not equivalent to either healthy or treatment-naive PMOP. The aim of the present observational study was to assess the effects of TPTD treatment in PMOP (20 μg, once daily) at 6 (TPTD 6m; n = 28, age 65 ± 7.3 years), and 24 (TPTD 24m; n = 32, age 67.4 ± 6.15 years) months on bone quality indices at actively forming trabecular surfaces (with fluorescent double labels). Data from the TPTD-treated PMOP patients were compared with those in healthy adult premenopausal women (HC; n = 62, age 40.5 ± 10.6 years), and PMOP receiving placebo (PMOP-PLC; n = 94, age 70.6 ± 4.5 years). Iliac crest biopsies were analyzed by Raman microspectroscopy at three distinct tissue ages: mid-distance between the second label and the bone surface, mid-distance between the two labels, and 1 μm behind the first label. Mineral to matrix ratio (MM), mineral maturity/crystallinity (MMC), tissue water (TW), glycosaminoglycan (GAGs), and pyridinoline (Pyd) content were determined. Outcomes were compared by ANCOVA with subject age and tissue age as covariates, and health status as a fixed factor, followed by Sidak's post-hoc testing (significance assigned to p 0.05). Both TPTD groups increased MM compared to PMOP-PLC. While TPTD 6m had values similar to HC, TPTD 24m had higher values compared to either HC or TPTD 6m. Both TPTD groups had lower MMC values compared to PMOP-PLC and similar to HC. TPTD 6m patients had higher TW content compared to HC, while TPTD 24m had values similar to HC and lower than either PMOP-PLC or TPTD 6m. Both TPTD groups had lower GAG content compared to HC group, while TPTD 6m had higher values compared to PMOP-PLC. Finally, TPTD 6m patients had higher Pyd content compared to HC and lower compared to PMOP-PLC, while TPTD 24m had lower values compared to PMOP-PLC and TPTD 6m, and similar to HC group. The results of the present study indicate that effects of TPTD on forming trabecular bone quality indices depend on treatment duration. At the recommended length of 24 m, TPTD restores bone mineral and organic matrix quality indices (MMC, TW, Pyd content) to premenopausal healthy (HC) levels.

MIL-STD-1553 is a military standard that defines the specification of a serial communication bus that has been implemented in military and aerospace avionic platforms for over 40 years. MIL-STD-1553 was designed for a high level of fault tolerance while less attention was paid to cyber security issues. Thus, as indicated in recent studies, it is exposed to various threats. In this article, we suggest enhancing the security of MIL-STD-1553 communication buses by integrating a machine learning-based intrusion detection system (IDS); such an IDS will be capable of detecting cyber attacks in real time. The IDS consists of two modules: 1) a remote terminal (RT) authentication module that detects illegitimately connected components and data transfers and 2) a sequence-based anomaly detection module that detects anomalies in the operation of the system. The IDS showed high detection rates for both normal and abnormal behavior when evaluated in a testbed using real 1553 hardware, as well as a very fast and accurate training process using logs from a real system. The RT authentication module managed to authenticate RTs with +0.99 precision and +0.98 recall; and detect illegitimate component (or a legitimate component that impersonates other components) with +0.98 precision and +0.99 recall. The sequence-based anomaly detection module managed to perfectly detect both normal and abnormal behavior. Moreover, the sequence-based anomaly detection module managed to accurately (i.e., zero false positives) model the normal behavior of a real system in a short period of time ( $\sim$ 22 s).

S. pneumoniae carriage by children is a major source of pneumococcal transmission, and the initial step prior to infection. Pilus type 1, reported in ~30% of pneumococcal strains in the pre-vaccine era, contributes to pneumococcal colonization and virulence. In this study, we report the impact of the pneumococcal conjugate vaccine (PCV), PCV7/PCV13 sequential implementation on serotype distribution, and on the prevalence of piliated strains among carried pneumococci during the pre- and post-vaccine eras.During 2002-2016, 12 repeated cross-sectional surveillances of nasopharyngeal S. pneumoniae carriage were conducted among 8,473 children5.5 years old visiting primary care physicians in Central Israel. Seven biannual surveillances in the pre-PCV period, 2 surveillances after PCV7 was licensed but before implementation in the National Immunization Plan, and 3 additional surveillances in the post-PCV period. S. pneumoniae serotype distribution and prevalence of piliated strains were assessed.Carriage of S. pneumoniae was relatively stable (45.4%). The prevalence of serotypes included in PCV13 was 65.7%, in the pre-vaccine period and the pilus was present in 26.4% of isolates. The distribution of serotypes and the pilus prevalence in the pre-PCV period was relatively stable except for a decrease in prevalence of piliated 19F, observed following the first study year. Following PCV7/PCV13 implementation, vaccine type 13 (VT13) strains were nearly eliminated to 3.3% by 2016. Piliated strains, which were primarily of VT13 serotypes, initially followed a similar trend and were nearly eliminated by 2014 (1.7%). Yet, two years later, pilus prevalence re-emerged among non-VT strains to 12.8% of all pneumococci.Following PCV implementation, a dramatic and rapid decrease in VT strains prevalence was observed with a concomitant increase in non-VT strains. Piliated strains were nearly eliminated, yet re-emerged 7 years following PCV7/PCV13 implementation in various non-VT strains. This suggests that the pilus confers an advantage in colonization.

Background Evaluation of a child with POC/OC is complicated due difficulties in physical examination and risks of imaging by computed tomography. Method Retrospective review of children 0-16 years admitted to the pediatric emergency department for POC/OC from 2009 to 2019. Results Ten years study period, 243 children younger than 16 years presented to the pediatric emergency department with a diagnosis of POC/OC. OC was documented in 51 (20.6%) patients. The mean age was 7.8 years (±4.3 years). Fever (80.4%), upper respiratory tract infection (43%), swelling of both eyelids (96%), proptosis (33.3%), and tenderness on percussion (24.5%) were more common in comparison to POC (P = 0.0001, 0.03, 0.0001, 0.0001, 0.0001 respectively). All children with suspected diagnosis of OC underwent computed tomography scan. POC accounted for 196 patients. Mean age was 4.6 (±4.3) years. Twenty percent of the cases were recorded as local trauma or insect bite in the infected eye.Mean leukocyte count in the OC group had higher mean of 15.2 (10/L) versus 13.4(10/L) (P = 0.05), absolute neutrophil count was significantly higher in the OC 11.3(10/L) versus 7.2(10/L) (P = 0.0001) whereas the lymphocyte count was higher in the POC 4.5(10/L) versus 2.4(10/L) (P = 0.0001), NLR of 0.318 correlates with orbital cellulitis with sensitivity of 75.5% and specificity of 77.4%.Patients with OC had mean C-reactive protein levels of 11.7 (mg/dL) versus 4.9(mg/dL) (P = 0.0001), erythrocyte sedimentation rate was elevated in the OC 53.6 (cm/h) versus 36.4 (cm/h) (P = 0.02).Based on the aforementioned study a risk calculator for OC was formulated with 6 major variables. Conclusions Differentiation between POC/OC is cardinal. This study highlights the importance of ancillary laboratory tests especially C-reactive protein in the assessment of infections of the eye.

Lead-based halide perovskite crystals are shown to have strongly anharmonic structural dynamics. This behavior is important because it may be the origin of their exceptional photovoltaic properties. The double perovskite, Cs2AgBiBr6, has been recently studied as a lead-free alternative for optoelectronic applications. However, it does not exhibit the excellent photovoltaic activity of the lead-based halide perovskites. Therefore, to explore the correlation between the anharmonic structural dynamics and optoelectronic properties in lead-based halide perovskites, the structural dynamics of Cs2AgBiBr6 are investigated and are compared to its lead-based analog, CsPbBr3. Using temperature-dependent Raman measurements, it is found that both materials are indeed strongly anharmonic. Nonetheless, the expression of their anharmonic behavior is markedly different. Cs2AgBiBr6 has well-defined normal modes throughout the measured temperature range, while CsPbBr3 exhibits a complete breakdown of the normal-mode picture above 200 K. It is suggested that the breakdown of the normal-mode picture implies that the average crystal structure may not be a proper starting point to understand the electronic properties of the crystal. In addition to our main findings, an unreported phase of Cs2AgBiBr6 is also discovered below approximate to 37 K. Funding Agencies|European Research Concil [850041 - ANHARMONIC]; Alexander von Humboldt FoundationAlexander von Humboldt Foundation; Department of Atomic Energy, Government of IndiaDepartment of Atomic Energy (DAE) [RTI 4007]; SERB IndiaDepartment of Science & Technology (India)Science Engineering Research Board (SERB), India [CRG/2020/003877]; Swedish Research Council (VR)Swedish Research Council [2020-04630, 2021-00486]; Swedish Research CouncilSwedish Research CouncilEuropean Commission [2018-05973]

Osteoporosis in premenopausal women with intact gonadal function and no known secondary cause of bone loss is termed idiopathic osteoporosis (IOP). Women with IOP diagnosed in adulthood have profound bone structural deficits and often report adult and childhood fractures, and family history of osteoporosis. Some have very low bone formation rates (BFR/BS) suggesting osteoblast dysfunction. These features led us to investigate potential genetic etiologies of bone fragility. In 75 IOP women (aged 20–49) with low trauma fractures and/or very low BMD who had undergone transiliac bone biopsies, we performed Whole Exome Sequencing (WES) using our variant analysis pipeline to select candidate rare and novel variants likely to affect known disease genes. We ran rare-variant burden analyses on all genes individually and on phenotypically-relevant gene sets. For particular genes implicated in osteoporosis, we also assessed the frequency of all (including common) variants in subjects versus 6540 non-comorbid female controls. The variant analysis pipeline identified 4 women with 4 heterozygous variants in LRP5 and PLS3 that were considered to contribute to osteoporosis. All 4 women had adult fractures, and 3 women also had multiple fractures, childhood fractures and a family history of osteoporosis. Two women presented during pregnancy/lactation. In an additional 4 subjects, 4 different relevant Variants of Uncertain Significance (VUS) were detected in the genes FKBP10, SLC34A3, and HGD. Of the subjects with VUS, 2 had multiple adult fractures, childhood fractures, and presented during pregnancy/lactation, and 2 had nephrolithiasis. BFR/BS varied among the 8 subjects with identified variants; BFR/BS was quite low in those with variants that are likely to have adverse effects on bone formation. The analysis pipeline did not discover candidate variants in COL1A1, COL1A2, WNT, or ALPL. Although we found several novel and rare variants in LRP5, cases did not have an increased burden of common LRP5 variants compared to controls. Cohort-wide collapsing analysis did not reveal any novel disease genes with genome-wide significance for qualifying variants between controls and our 75 cases. In summary, WES revealed likely pathogenic variants or relevant VUS in 8 (11%) of 75 women with IOP. Notably, the genetic variants identified were consistent with the affected women's diagnostic evaluations that revealed histological evidence of low BFR/BS or biochemical evidence of increased bone resorption and urinary calcium excretion. These results, and the fact that the majority of the women had no identifiable genetic etiology, also suggest that the pathogenesis of and mechanisms leading to osteoporosis in this cohort are heterogeneous Future research is necessary to identify both new genetic and non-genetic etiologies of early-onset osteoporosis.

Pregnancy and lactation-associated osteoporosis (PLO) is a rare, severe, early form of osteoporosis in which young women present with fractures, usually multiple vertebral fractures, during late pregnancy or lactation. In studies of idiopathic osteoporosis (IOP) in premenopausal women, we enrolled 78 women with low-trauma fractures and 40 healthy controls, all with normal menses and no secondary cause of bone loss. In 15 of the affected women, the PLO subgroup, fractures had occurred during late pregnancy or lactation. We hypothesized that clinical, bone structural, and metabolic characteristics would differ between women with PLO and those with (non-PLO) IOP and controls. All were evaluated > 12 months postpartum, when structural and remodeling characteristics would be expected to reflect baseline premenopausal status rather than transient postpartum changes. As previously reported, affected subjects (PLO and IOP) had BMD and microarchitectural deficiencies compared to controls. Women with PLO did not differ from those with IOP in terms of age, BMI, body fat, menarcheal age, parity, or age at first pregnancy. However, women with PLO had a more severe clinical presentation than those with IOP: more fractures (5.5 ± 3.3 versus 2.6 ± 2.1; p = 0.005); more vertebral fractures (80% versus 17%; p < 0.001); and higher prevalence of multiple fractures. BMD deficits were more profound and cortical width tended to be lower in PLO. PLO subjects also had significantly lower tissue-level mineral apposition rate and bone formation rates (0.005 ± 0.005 versus 0.011 ± 0.010 mm2 /mm/year; p = 0.006), as well as lower serum P1NP (33 ± 12 versus 44 ± 18 µg/L; p = 0.02) and CTX (257 ± 102 versus 355 ± 193 pg/mL; p = 0.01) than IOP. The finding that women with PLO have a low bone remodeling state assessed more than a year postpartum increases our understanding of the pathogenic mechanism of PLO. We conclude that women with PLO may have underlying osteoblast functional deficits which could affect their therapeutic response to osteoanabolic medications. © 2019 American Society for Bone and Mineral Research.

Bone's ability to adapt is governed by the network of embedded osteocytes, which inhabit individual pores called lacunae. The morphology of these lacunae and their resident osteocytes are known to change with age and diseases such as postmenopausal osteoporosis. However, it is unclear whether alterations in lacunar morphology are present in younger populations with osteoporosis. To investigate this, we implemented a previously validated methodology to image and quantify the three-dimensional morphometries of lacunae on a large scale with ultra-high-resolution micro-computed tomography (microCT) in transiliac bone biopsies from three groups of premenopausal women: control n = 39; idiopathic osteoporosis (IOP) n = 45; idiopathic low BMD (ILBMD) n = 19. Lacunar morphometric parameters were measured in both trabecular and cortical bone such as lacunar density (Lc.N/BV), lacunar volume (Lc.V), and lacunar sphericity (Lc.Sr). These were then compared against each other and also with previously measured tissue morphometries such as bone volume density (BV/TV), trabecular separation (Tb.Sp), trabecular number (Tb.N), and others. We detected no differences in lacunar morphology between the IOP, ILBMD and healthy premenopausal women. In contrast, we did find significant differences between lacunar morphologies including Lc.N/BV, Lc. V, and Lc. Sr in cortical and trabecular regions within all three groups (p < 0.001), which was consistent with our previous findings on a subgroup of the healthy group. Furthermore, we discovered strong correlations between Lc. Sr from trabecular regions with the measured BV/TV (R = −0.90, p < 0.05). The findings and comprehensive lacunar dataset we present here will be a crucial foundation for future investigations of the relationship between osteocyte lacunar morphology and disease., Bone, 160, ISSN:8756-3282

Although presentation with osteoporosis in the premenopausal years is quite rare, fractures during this time can cause significant morbidity. Diagnostic criteria for premenopausal women differ substantially from those in postmenopausal women and interpretation of bone mineral density (BMD) measurements also differs. In premenopausal women, interpretation of BMD must take into account both the timing of peak bone mass accrual and expected changes related to reproductive events. Evaluation in this population focuses on a search for possible secondary/pathologic causes of bone fragility and bone loss. Some women have no cause found after extensive evaluation and may have primary forms of osteoporosis. They may also exhibit the effects of pathologic conditions or medication exposures that are no longer present at the time of initial evaluation. Initial management in premenopausal women with osteoporosis should focus on addressing underlying secondary causes, whenever possible. Some women, particularly those who have multiple or recurrent fragility fractures or ongoing causes of bone loss, may benefit from medical treatment. Data to inform pharmacologic treatment decisions are sparse; studies are often small and have provided very little evidence regarding the effects of therapeutic interventions on fracture risk. This chapter discusses the epidemiology, classification, and evaluation of premenopausal osteoporosis, as well as the unique considerations for use of BMD by dual X-ray absorptiometry in premenopausal patients. The chapter will also discuss considerations for pharmacologic treatment in this population.

Significance Only recently have multiple, anabolic, bone-forming agents become available, raising the possibility that osteoporosis might be more effectively treated by combinatorial or sequential treatments rather than single agents. The discovery of osteolectin raised two important questions in this regard. First, what is the epistatic relationship between these agents? Second, would osteolectin have additive effects if combined with another agent? Our discovery that osteolectin mediates part of the effect of parathyroid hormone (PTH) on bone formation identifies a new mechanism by which PTH acts. The observation that PTH and osteolectin have additive effects provides proof-of-principle that combinatorial use can increase osteogenesis., We previously described a new osteogenic growth factor, osteolectin/Clec11a, which is required for the maintenance of skeletal bone mass during adulthood. Osteolectin binds to Integrin α11 (Itga11), promoting Wnt pathway activation and osteogenic differentiation by leptin receptor+ (LepR+) stromal cells in the bone marrow. Parathyroid hormone (PTH) and sclerostin inhibitor (SOSTi) are bone anabolic agents that are administered to patients with osteoporosis. Here we tested whether osteolectin mediates the effects of PTH or SOSTi on bone formation. We discovered that PTH promoted Osteolectin expression by bone marrow stromal cells within hours of administration and that PTH treatment increased serum osteolectin levels in mice and humans. Osteolectin deficiency in mice attenuated Wnt pathway activation by PTH in bone marrow stromal cells and reduced the osteogenic response to PTH in vitro and in vivo. In contrast, SOSTi did not affect serum osteolectin levels and osteolectin was not required for SOSTi-induced bone formation. Combined administration of osteolectin and PTH, but not osteolectin and SOSTi, additively increased bone volume. PTH thus promotes osteolectin expression and osteolectin mediates part of the effect of PTH on bone formation.

The coronavirus disease 2019 (COVID-19) outbreak introduced unprecedented health-risks, as well as pressure on the economy, society, and psychological well-being due to the response to the outbreak. In a preregistered study, we hypothesized that the intense experience of the outbreak potentially induced stress-related brain modifications in the healthy population, not infected with the virus. We examined volumetric changes in 50 participants who underwent MRI scans before and after the COVID-19 outbreak and lockdown in Israel. Their scans were compared with those of 50 control participants who were scanned twice prior to the pandemic. Following COVID-19 outbreak and lockdown, the test group participants uniquely showed volumetric increases in bilateral amygdalae, putamen, and the anterior temporal cortices. Changes in the amygdalae diminished as time elapsed from lockdown relief, suggesting that the intense experience associated with the pandemic induced transient volumetric changes in brain regions commonly associated with stress and anxiety. The current work utilizes a rare opportunity for real-life natural experiment, showing evidence for brain plasticity following the COVID-19 global pandemic. These findings have broad implications, relevant both for the scientific community as well as the general public.

Type 2 diabetes mellitus (T2DM) patients are at an increased risk of fracture despite normal to high bone mineral density (BMD) values. In this cross-sectional study we establish bone compositional properties in tetracycline labeled iliac crest biopsies from premenopausal women diagnosed with T2DM (N = 26). Within group comparisons were made as a function of tissue age (TA), presence of chronic complications (CC), glycosylated haemoglobin (HbA1c) levels, and morphometric fracture (MFx). We also compared these data at actively trabecular bone forming surfaces against sex- and age-matched healthy controls (N = 32). The bone quality indices determined by Raman microspectroscopic analysis were: mineral/matrix (MM), tissue water content (nanoporosity; NanoP), mineral maturity/crystallinity (MMC), and glycosaminoglycan (GAG), pyridinoline (Pyd), N-(carboxymethyl)lysine (CML), and pentosidine (PEN) content. Within the T2DM group, at the oldest tissue, CML and PEN contents were significantly elevated in the cancellous compared to cortical compartment. The outcomes were not dependent on MFx. On the other hand, both were significantly elevated in patients with CC, as well as those with HbA1c levels > 7%. At actively forming surfaces, the cortical compartment had higher NanoP compared to cancellous. Still within the T2DM group, patients with MFx had significantly elevated MM and GAGs compared to the ones that did not. At actively forming trabecular surfaces, compared to healthy women, T2DM patients had elevated GAGs content and MMC. The results of this study indicate increased AGEs in those with poor glycation control and chronic complications. Additionally, T2DM patients had elevated MMC and decreased GAGs content compared to healthy controls. These alterations may be contributing to the T2DM inherent elevated fracture risk and suggest a role for hyperglycemia on bone quality.

Context Premenopausal women with idiopathic osteoporosis (IOP) have abnormal skeletal microarchitecture and variable tissue-level bone formation rate (BFR). Objectives Compare 6 months (M) of teriparatide versus placebo on areal bone mineral density (aBMD) by dual-energy x-ray absorptiometry (DXA), bone turnover markers (BTMs) and BFR at 3M by quadruple-labeled transiliac biopsy. Characterize 12M and 24M effects of teriparatide on aBMD and whether BTMs and BFR predict response. Design 6M phase 2 randomized controlled trial (RCT) followed by open extension. Setting Tertiary referral centers. Patients Premenopausal women with IOP. Interventions A total of 41 women were randomized to either teriparatide 20 mcg (n = 28) or placebo (n = 13). After 6M, those on placebo switched to teriparatide for 24M; those on teriparatide continued for 18M. Main Outcome Measures 6M RCT: Between-group differences in lumbar spine (LS) aBMD (percent change from baseline), 3M BFR, and hypercalcemia. Open-label extension: Within-group change in LS aBMD over 12M and 24M. Secondary outcomes included aBMD change at other sites and relationship between BTMs, BFR, and changes in aBMD. Findings Over 6M, LS aBMD increased by 5.5% (95% CI: 3.83, 7.19) in teriparatide and 1.5% (95% CI: −0.73, 3.83) in placebo (P = 0.007). There were increases in 3M BTMs, and BFR (cancellous and endocortical BFR: between-groups P = 0.004). Over 24M, teriparatide increased LS aBMD by 13.2% (95% CI: 10.3, 16.2), total hip by 5.2% (95% CI: 3.7, 6.7) and femoral neck by 5.0% (95% CI: 3.2, 6.7; all P ≤ 0.001). Serum N-terminal propeptides of procollagen type 1 (P1NP) and 3M endocortical BFR were moderately associated with LS aBMD response. Teriparatide was well-tolerated. Conclusions Teriparatide increased BFR and formation markers and was associated with marked aBMD improvements in most premenopausal women (82%) with IOP.

X-linked hypophosphatemia (XLH) caused by PHEX mutations results in elevated serum FGF23 levels, renal phosphate wasting and low 1,25-dihydroxyvitamin D. The glycophosphoprotein osteopontin, a potent inhibitor of mineralization normally degraded by PHEX, accumulates within the bone matrix. Conventional therapy consisting of supplementation with phosphate and vitamin D analogs is burdensome and the effects on bone material poorly characterized. We analyzed transiliac bone biopsies from four adult patients, two of them severely affected due to no diagnosis and no treatment until adulthood. We used light microscopy, qBEI and FTIRI to study histology, histomorphometry, bone mineralization density distribution, properties of the organic matrix and size of hypomineralized periosteocytic lesions. Non-treatment resulted in severe osteomalacia, twice the amount of mineralized trabecular volume, multiple osteon-like perforations, continuity of lamellae from mineralized to unmineralized areas and distinctive patches of woven bone. Periosteocytic lesions were larger than in treated patients. The latter had nearly normal osteoid thicknesses, although surface was still elevated. The median calcium content of the matrix was always within normal range, although the percentage of lowly mineralized bone areas was highly increased in non-treated patients, resulting in a marked heterogeneity in mineralization. Divalent collagen cross-links were evident independently of the mineral content of the matrix. Broad osteoid seams lacked measurable pyridinoline, a mature trivalent cross-link and exhibited considerable acidic lipid content, typically found in matrix vesicles. Based on our results, we propose a model that possibly integrates the relationship between the observed mineralization disturbances, FGF23 secretion and the known osteopontin accumulation in XLH.

Although osteoporosis occurs most commonly after menopause, premenopausal women can also present with low-trauma fractures or low bone mineral density (BMD). Diagnosis of osteoporosis and management in this population are different than for postmenopausal women. This chapter reviews the definition and epidemiology of premenopausal osteoporosis. It also addresses the interpretation of Dual X-ray Absorptiometry (DXA) results in premenopausal women. Furthermore, it describes normal bone mineral metabolism in young women including peak bone mass accrual and physiological changes of pregnancy and lactation that may affect interpretation of results.

Ultra-high-resolution imaging of the osteocyte lacuno-canalicular network (LCN) three-dimensionally (3D) in a high-throughput fashion has greatly improved the morphological knowledge about the constituent structures – positioning them as potential biomarkers. Technologies such as serial focused ion beam/scanning electron microscopy (FIB/SEM) and confocal scanning laser microscopy (CLSM) can image in extremely high resolution, yet only capture a small number of lacunae. Synchrotron radiation computed tomography (SR-CT) can image with both high resolution and high throughput but has a limited availability. Desktop micro-computed tomography (micro-CT) provides an attractive balance: high-throughput imaging on the micron level without the restrictions of SR-CT availability. In this study, accuracy, reproducibility, and sensitivity of large-scale quantification of human osteocyte lacunar morphometries were assessed by ultra-high-resolution desktop micro-computed tomography. For this purpose, thirty-one transiliac human bone biopsies containing trabecular and cortical regions were imaged using ultra-high-resolution desktop micro-CT at a nominal isotropic voxel resolution of 1.2 µm. The resulting 3D images were segmented, component labeled, and the following morphometric parameters of 7.71 million lacunae were measured: Lacunar number (Lc.N), density (Lc.N/BV), porosity (Lc.TV/BV), volume (Lc.V), surface area (Lc.S), surface area to volume ratio (Lc.S/Lc.V), stretch (Lc.St), oblateness (Lc.Ob), sphericity (Lc.Sr), equancy (Lc.Eq), and angle (Lc.θ). Accuracy was quantified by comparing automated lacunar identification to manual identification. Mean true positive rate (TPR), false positive rate (FPR), and false negative rate (FNR) were 89.0%, 3.4%, and 11.0%, respectively. Regarding the reproducibility of lacunar morphometry from repeated measurements, precision errors were low (0.2–3.0%) and intraclass correlation coefficients were high (0.960–0.999). Significant differences between cortical and trabecular regions (p), and local lacunar volume (), all of which demonstrate the sensitivity of the method and are possible biomarker candidates. This study provides the foundation required for future large-scale morphometric studies using ultra-high-resolution desktop micro-CT and high-throughput analysis of millions of osteocyte lacunae in human bone samples., Bone, 152, ISSN:8756-3282

We have previously reported that premenopausal women with idiopathic osteoporosis (IOP) have profound microarchitectural deficiencies and heterogeneous bone remodeling. Those with the lowest bone formation rate have higher baseline serum insulin-like growth factor-1 (IGF-1) levels and less robust response to teriparatide. Because IGF-1 stimulates bone formation and is critical for teriparatide action on osteoblasts, these findings suggest a state of IGF-1 resistance in some IOP women. To further investigate the hypothesis that osteoblast and IGF-1-related mechanisms mediate differential responsiveness to teriparatide in IOP, we studied circulating osteoblast progenitor (COP) cells and their IGF-1 receptor (IGF-1R) expression. In premenopausal women with IOP, peripheral blood mononuclear cells (PBMCs) were obtained at baseline (n = 25) and over 24 months of teriparatide treatment (n = 11). Flow cytometry was used to identify and quantify COPs (non-hematopoetic lineage cells expressing osteocalcin and RUNX2) and to quantify IGF-1R expression levels. At baseline, both the percent of PBMCs that were COPs (%COP) and COP cell-surface IGF-1R expression correlated directly with several histomorphometric indices of bone formation in tetracycline-labeled transiliac biopsies. In treated subjects, both %COP and IGF-1R expression increased promptly after teriparatide, returning toward baseline by 18 months. Although neither baseline %COP nor increase in %COP after 3 months predicted the bone mineral density (BMD) response to teriparatide, the percent increase in IGF-1R expression on COPs at 3 months correlated directly with the BMD response to teriparatide. Additionally, lower IGF-1R expression after teriparatide was associated with higher body fat, suggesting links between teriparatide resistance, body composition, and the GH/IGF-1 axis. In conclusion, these assays may be useful to characterize bone remodeling noninvasively and may serve to predict early response to teriparatide and possibly other bone formation-stimulating medications. These new tools may also have utility in the mechanistic investigation of teriparatide resistance in premenopausal IOP and perhaps in other populations. © 2017 American Society for Bone and Mineral Research.

Most premenopausal women with low trauma fracture(s) or low BMD have a secondary cause of osteoporosis or bone loss. Women who present with unexplained fractures or low BMD should have a thorough clinical and laboratory evaluation to search for known causes of fractures and/or bone loss. Where possible, treatment of the underlying cause should be the focus of management. Premenopausal women with an ongoing cause of bone loss and those who have had, or continue to have, low trauma fractures may require pharmacological intervention. Clinical trials provide evidence of benefits of bisphosphonates and teriparatide for bone mineral density in several types of premenopausal osteoporosis, but studies are small and do not provide evidence regarding fracture risk reduction.

Background Biofuels derived from lignocellulosic biomass are a viable alternative to fossil fuels required for transportation. Following plant biomass pretreatment, the furan derivative furfural is present at concentrations which are inhibitory to yeasts. Detoxification of furfural is thus important for efficient fermentation. Here, we searched for new genetic attributes in the fungus Neurospora crassa that may be linked to furfural tolerance. The fact that furfural is involved in the natural process of sexual spore germination of N. crassa and that this fungus is highly amenable to genetic manipulations makes it a rational candidate for this study. Results Both hypothesis-based and unbiased (random promotor mutagenesis) approaches were performed to identify N. crassa genes associated with the response to furfural. Changes in the transcriptional profile following exposure to furfural revealed that the affected processes were, overall, similar to those observed in Saccharomyces cerevisiae. N. crassa was more tolerant (by ~ 30%) to furfural when carboxymethyl cellulose was the main carbon source as opposed to sucrose, indicative of a link between carbohydrate metabolism and furfural tolerance. We also observed increased tolerance in a Δcre-1 mutant (CRE-1 is a key transcription factor that regulates the ability of fungi to utilize non-preferred carbon sources). In addition, analysis of aldehyde dehydrogenase mutants showed that ahd-2 (NCU00378) was involved in tolerance to furfural as well as the predicted membrane transporter NCU05580 (flr-1), a homolog of FLR1 in S. cerevisiae. Further to the rational screening, an unbiased approach revealed additional genes whose inactivation conferred increased tolerance to furfural: (i) NCU02488, which affected the abundance of the non-anchored cell wall protein NCW-1 (NCU05137), and (ii) the zinc finger protein NCU01407. Conclusions We identified attributes in N. crassa associated with tolerance or degradation of furfural, using complementary research approaches. The manipulation of the genes involved in furan sensitivity can provide a means for improving the production of biofuel producing strains. Similar research approaches can be utilized in N. crassa and other filamentous fungi to identify additional attributes relevant to other furans or toxic chemicals.

Adipose tissue (AT) mass, especially visceral (VAT), is reduced in active acromegaly and rises with treatment. Although the effect of acromegaly and its therapy on marrow AT(MAT) is unknown, data in other populations and in vitro, suggest a reciprocal relationship between GH and marrow adiposity. In other groups, VAT and MAT are associated with reduced bone quality and increased vertebral fracture (VF) risk. Therefore, since acromegaly patients have an increased VF incidence, we examined the relationships of VAT and MAT to bone quality in acromegaly. We studied 65 acromegaly subjects (40 men, 25 women, range 18.7-74 yr.) before (n=20) or before and after (n=45) acromegaly therapy by total body multi-slice MRI(n=159)(measurement of VAT, subcutaneous (SAT) and total (TAT) adipose tissue mass), DXA (BMD (n=120) and body composition (n=145)) and HRpQCT (n=35) (microarchitecture of the tibia and radius). Marrow lipid spectra of the tibial diaphysis were acquired by 1H MRS (PRESS technique)(1.5T MR scanner, Philips) and percentages of bone marrow lipids were quantified (n=53). GH and IGF-1 (n=159) and bone turnover markers (BTM)(n=49) were measured. We examined the relationship between MAT or VAT and GH, IGF-1, age, weight, mass of other MRI measured AT depots, and selected DXA and HRpQCT parameters previously shown to differ in acromegaly compared to healthy subjects and to be associated in other groups with fracture. Data were analyzed by Pearson correlation and the generalized estimating equation (GEE). MAT directly correlated with VAT (r=.249, p=.023) and by HRpQCT (n=13) with bone size (radius: total area (r=.678, p=.01), tibia: total area (r=.535, p=.05)) and trabecular number (r=.543, p=.055). VAT was inversely associated with GH (β= -.017, p

Diffusing alpha-emitters radiation therapy (DaRT) is the only known method for treating solid tumors with highly destructive alpha radiation. More importantly, as a monotherapy, DaRT has been shown to induce a systemic antitumor immune response following tumor ablation. Here, immunomodulatory strategies to boost the antitumor immune response induced by DaRT, and the response specificity, were investigated in the colon cancer CT26 mouse model. Local treatment prior to DaRT, with the TLR3 agonist poly I:C, was sufficient to inhibit tumor growth relative to poly I:C or DaRT alone. DaRT used in combination with the TLR9 agonist CpG, or with the TLR1/2 agonist XS15 retarded tumor growth and increased tumor-rejection rates, compared to DaRT alone, curing 41% and 20% of the mice, respectively. DaRT in combination with CpG, the Treg inhibitor cyclophosphamide, and the MDSC inhibitor sildenafil, cured 51% of the animals, compared to only 6% and 0% cure when immunomodulation or DaRT was used alone, respectively. Challenge and Winn assays revealed that these high cure rates involved a specific immunological memory against CT26 antigens. We suggest that DaRT acts in synergy with immunomodulation to induce a specific and systemic antitumor immune response. This strategy may serve as a safe and efficient method not only for tumor ablation, but also for in situ vaccination of cancer patients.

MIL-STD-1553 is a military standard that defines the physical and logical layers, and a command/response time division multiplexing of a communication bus used in military and aerospace avionic platforms for more than 40 years. As a legacy platform, MIL-STD-1553 was designed for high level of fault tolerance while less attention was taken with regard to security. Recent studies already addressed the impact of successful cyber-attacks on aerospace vehicles that are implementing MIL-STD-1553. In this work we present a security analysis of MIL-STD-1553, which enumerates the assets and threats to the communication bus, as well as defines the attacker’s profile.

Primary immunodeficiencies (PIDs) are a heterogeneous group of monogenic inborn errors of immunity. The genetic causes of these diseases can be identified using whole exome sequencing (WES). Here, DNA samples from 106 patients with a clinical suspicion of PID were subjected to WES in order to test the diagnostic yield of this test in a highly consanguineous community. A likely genetic diagnosis was achieved in 70% of patients. Several factors were considered to possibly influence the diagnostic rate of WES among our cohort including early age, presence of consanguinity, family history suggestive of PID, the number of family members who underwent WES and the clinical phenotype of the patient. The highest diagnostic rate was in patients with combined immunodeficiency or with a syndrome. Notably, WES findings altered the clinical management in 39% (41/106) of patients in our cohort. Our findings support the use of WES as an important diagnostic tool in patients with suspected PID, especially in highly consanguineous communities.

To evaluate changes in the bone turnover markers CTx and P1NP during 6 months' use of novel continuous contraceptive vaginal rings delivering Nestorone (NES) 200 mcg/day and three doses of estradiol (E2) (10, 20, and 40 mcg/day).This randomized trial enrolled 189 women who used two consecutive vaginal rings over 180 days. Frequent blood sampling permitted analysis of NES, E2, CTx and P1NP concentrations. The bone-turnover marker analyses included only women with complete sampling and excluded women with characteristics that might interfere with accurate measurement of bone markers such as afternoon sampling, poor ring compliance or recent pregnancy. We evaluated the change from baseline to 6 months in CTx and P1NP, stratified by ring dose and by average circulating E2 concentrations.One hundred fifty-one women completed the study, and 82 women had complete data available for the bone marker analyses; the three dosage groups were balanced with regard to baseline characteristics. E2 concentrations remained low throughout treatment, regardless of which dose ring the participant used. Individual CTx changes from baseline averaged 27±56% (p.01). Similarly, individual P1NP changes averaged 11±33% (p=.04). These increases were within the premenopausal reference ranges, and unrelated to treatment dose or to circulating E2 concentrations.The low E2 dose of these rings was associated with low E2 concentrations and modest increases in serum bone turnover makers. Because we have only 6-month bone turnover markers and no direct evidence of bone loss or bone density change, these results must be interpreted with caution.Nestorone, a 19-norprogesterone derivative, leads to complete ovarian suppression, which should yield excellent contraceptive effectiveness. To prevent potential adverse effects on bone, the NES contraceptive ring should be combined with higher doses of E2 than were assessed in this study.

The aldol condensation of aldehydes and α-bromo esters to prepare α-bromo-β-hydroxy esters is described. The presented procedure is simple and direct, and works with a range of aromatic aldehydes.

Bone strength depends on the amount of bone, typically expressed as bone mineral density (BMD), determined by dual-energy X-ray absorptiometry (DXA), and on bone quality. Bone quality is a multifactorial entity including bone structural and material compositional properties. The purpose of the present study was to examine whether bone material composition properties at actively-forming trabecular bone surfaces in health are dependent on subject age, and to contrast them with postmenopausal osteoporosis patients. To achieve this, we analyzed by Raman microspectroscopy iliac crest biopsy samples from healthy subjects aged 1.5 to 45.7 years, paired biopsy samples from females before and immediately after menopause aged 46.7 to 53.6 years, and biopsy samples from placebo-treated postmenopausal osteoporotic patients aged 66 to 84 years. The monitored parameters were as follows: the mineral/matrix ratio; the mineral maturity/crystallinity (MMC); nanoporosity; the glycosaminoglycan (GAG) content; the lipid content; and the pyridinoline (Pyd) content. The results indicate that these bone quality parameters in healthy, actively-forming trabecular bone surfaces are dependent on subject age at constant tissue age, suggesting that with advancing age the kinetics of maturation (either accumulation, or posttranslational modifications, or both) change. For most parameters, the extrapolation of models fitted to the individual age dependence of bone in healthy individuals was in rough agreement with their values in postmenopausal osteoporotic patients, except for MMC, lipid, and Pyd content. Among these three, Pyd content showed the greatest deviation between healthy aging and disease, highlighting its potential to be used as a discriminating factor.

Research on DNA binding antitumor agents has been classically steered by either non-covalent (DNA intercalation) or covalent (DNA alkylation) interactions. In this context bi-functional anticancer molecules are particularly attractive since they are capable of sequential DNA intercalation followed by DNA alkylation. Here we describe the synthesis and in vitro anticancer activity of bi-functional 1,8-naphthalimide N(4) and S(4)-derivatives. Cell viability assays indicate that our amonafide-N-mustard chimeras are selective, effective only on certain tumor cell lines, and less toxic toward non-malignant cells than the drug amonafide. The biological activities of the bi-functional derivatives presented here are encouraging and the compounds are suitable for further optimization and in vivo studies. Here we describe the synthesis and in vitro anticancer activity of three bi-functional 1,8-naphthalimide N(4) and S(4)-derivatives presenting both DNA intercalation and alkylation capabilities. Cell viability assays indicate that these amonafide-N-mustard chimeras are effective only on certain tumor cell lines and are less toxic towards non-malignant cells than their parent drug: amonafide.